Renal epithelial cells are normally quiescent, but can increase their growth rate. In some situations, such as following an acute renal injury, the cell growth is essential to repairing the damaged epithelium, and appears tightly regulated. In contrast, unregulated, and ultimately destructive, growth occurs in renal cancer, polycystic kidney disease, and the progressive loss of renal function associated with loss of renal mass, diabetes mellitus, and most forms of glomerular injury. The growth changes that occur involve both hyperplasia (resulting in an increase in cell number) and hypertrophy (resulting in an increase in cell size). Using in vitro systems, two mechanisms of renal epithelial cell hypertrophy have been characterized; One involves regulation of the cell cycle process (referred to as being cell cycle-dependent) and is mediated by growth factors and cytokines, and the other is independent of cell cycle processes and mediated by agents that alkalinize intravesicular compartments, such as NH4C1. Using in vivo renal growth models, we have shown that: 1) Compensatory renal growth following uninephrectomy is a hypertrophic growth process that involves primarily activation of cyclin D kinase, without an increase in BrdU incorporation, and is not affected by inhibiting ammoniagenesis, suggesting that a cell cycle-dependent mechanism is involved; 2) Diabetes-induced renal growth involves an initial hyperplastic growth phase associated with activation of both G, kinase and an increase in BrdU incorporation, followed by a hypertrophic growth phase associated with continued activation of cyclin D kinase, inhibition of cyclin E kinase, and inhibition of BrdU incorporation; 3) The renal growth associated with chronic hypokalemia can be reversed when ammoniagenesis is inhibition by an alkaline diet, suggesting a cell cycle-independent mechanism of growth; and 4) In transgenic mice in which the endothelin B receptor has been knocked out, uninephrectomy does not lead to hypertrophy. Aim 1 will continue to characterize the role of cell cycle proteins in compensatory renal growth. Aim 2 will focus of diabetes-induced hypertrophy. Studies will examine the regulation of the cell cycle proteins in the switch between a hyperplastic and hypertrophic growth pattern. Studies will be done in 3 models of diabetes mellitus: streptozotocin-induced type I, in Nod mice (type I), and in db/db mice (type II). Studies will also be done to determine the role of the endothelin B receptor in diabetes-induced renal growth. Aim 3 will determine the mechanisms involved in the activation of cyclin D kinase and inhibition of cyclin E kinase in cell cycle-dependent hypertrophy. Aim 4 will determine if the endothelin B receptor plays a role in chronic metabolic acidosis and chronic potassium deficiency, models of renal hypertrophy thought to be mediated by the cell cycle-independent mechanism. Together these studies will afford us the opportunity to determine if direct regulation of cell cycle processes provides an avenue for therapeutic advances that will either improve upon the beneficial effects or reduce the detrimental sequelae of renal injury.